Resveratrol (trans-3,5,4'-trihydroxystilbene), a compound found largely in the skins of red grapes, is a component of Ko-jo-kon, an oriental medicine used to treat diseases of the blood vessels, heart [1,2], and liver [2]. It came to scientific attention only four years ago, however, as a possible explanation for the "French Paradox" -- the low incidence of heart disease among the French people, who eat a relatively high-fat diet [3]. Today, it is touted by manufacturers and being examined by scientific researchers as an antioxidant [4], an anti-cancer agent, and a phytoestrogen [5]. It is also being advertised on the Internet as "The French Paradox in a bottle." [A] Arkopharma, of Wallingford, Connecticut, even markets a red-wine extract antioxidant product called "French Parad'ox." This article reviews the recent research on resveratrol's physiologic activity.

Sources

While present in other plants, such as eucalyptus, spruce, and lily, and in other foods such as mulberries and peanuts, resveratrol's most abundant natural sources are Vitis vinifera, labrusca, and muscadine grapes, which are used to make wines. It occurs in the vines, roots, seeds, and stalks, but its highest concentration is in the skin [1], which contains 50-100 micrograms (µg) per gram [4]. Resveratrol is a phytoalexin, a class of antibiotic compounds produced as a part of a plant's defense system against disease [1]. For example, in response to an invading fungus, resveratrol is synthesized from p-coumaroyl CoA and malonyl CoA [2]. Since fungal infections are more common in cooler climates, grapes grown in cooler climates have a higher concentration [3].

The resveratrol content of wine is related to the length of time the grape skins are present during the fermentation process. Thus the concentration is significantly higher in red wine than in white wine, because the skins are removed earlier during white-wine production, lessening the amount that is extracted [3]. Grape juice, which is not a fermented beverage, is not a significant source of resveratrol. A fluid ounce of red wine averages 160 µg of resveratrol, compared to peanuts, which average 73 µg per ounce [6]. Since wine is the most notable dietary source, it is the object of much speculation and research.

Cardiovascular Effects

Many studies suggest that consuming alcohol (especially red wine) may reduce the incidence of coronary heart disease (CHD). Several studies have demonstrated that resveratrol is an effective antioxidant [7-10]. It inhibits lipid peroxidation of low-density lipoprotein (LDL) [7,8], prevents the cytotoxicity of oxidized LDL [7], and protects cells against lipid peroxidation [7]. It is thought that because it contains highly hydrophilic and lipophilic properties, it can provide more effective protection than other well-known antioxidants, such as vitamins C and E [7]. On the other hand, it is less effective than the antioxidants quercetin and epicatechin found in red wine [2]. Reduced platelet aggregation has also been demonstrated in studies on resveratrol, further contributing to its prevention of atherosclerosis [2,9]. To date, most of the research on resveratrol's antioxidant and anti-platelet properties has been done in vitro (in an artificial environment using test-tube or tissue-culture preparations). Further studies in animals and humans are necessary to determine whether resveratrol supplementation makes sense.

Cancer-Related Effects

Resveratrol is being studied to see how it affects the initiation, promotion, and progression of cancer. With regard to tumor initiation, it has been shown to act as an antioxidant by inhibiting free radical formation, and as an anti-mutagen in rat models [4]. Resveratrol appears to decrease tumor promotion activity by inhibiting cyclooxygenase-1 (COX-1) [4,11,12], an enzyme that converts arachidonic acid to pro-inflammatory substances that stimulate tumor-cell growth [3]. Studies related to progression have found that resveratrol induced human promyelocytic leukemia cell differentiation [4] and inhibited ribonucleotide reductase, an enzyme needed for DNA synthesis in proliferating cells [12]. One appealing characteristic of resveratrol's anti-cancer potential is its minimal toxicity to blood-forming cells [11]. More studies using both cellular and animal models are needed before any such data would be applicable to human use.

The similarity in structure between resveratrol and diethylstilbestrol (a synthetic estrogen) has prompted investigations into resveratrol's potential as a phytoestrogen (a plant compound that produces estrogen-like effects). However, these properties also stimulate the growth of human breast cancer cells [5]. This finding seems contrary to its other anticancer activities, and is a cause for concern.

The Bottom Line

Laboratory tests have clearly demonstrated that resveratrol may help prevent cardiovascular disease and cancer. However, there are several reasons why recommending a population-wide increase would be premature.

First, little is known about the absorption and clearance of resveratrol, the identities of its metabolic products, or its effects on the liver [5]. A study in rats showed that resveratrol is absorbed in the gut and has a high affinity for the heart and liver [13,14].

Second, the research on resveratrol has focused on its short-term effects [2] and has been dominated by in vitro studies on non-human models.

Third, its role as a potentiator of breast carcinomas may significantly limit its use, even for its "proven" benefits.

Finally, its main dietary source is red wine. Not only is its concentration in wine extremely variable, but recommending increased consumption of red wine to boost resveratrol intake could certainly do more harm than good. In spite of any beneficial aspects, red wine and other alcoholic beverages pose health risks that include liver damage and physical addiction.

The health-food industry is claiming that resveratrol is the wine component responsible for the "French Paradox." While taking resveratrol pills is certainly safer than heavy consumption of red wine, supplementing with unproven substances is generally unwise. At this point, occasional use of red wine seems far more prudent.

Bertelli AA and others. Evaluation of kinetic parameters of natural phytoalexin in resveratrol orally administered in wine to rats. Drugs under Experimental and Clinical Research 24:51-55, 1998.

Bertelli A and others. Plasma and tissue resveratrol concentrations and pharmacological activity. Drugs under Experimental and Clinical Research 24:133-138, 1998.

__________________

Mrs. McElderry is a dietitian who co-owns and operates several restaurants and threatre-pubs. Carolyn M. Klinge, Ph.D., Assistant Professor of Biochemistry and Molecular Biology, University of Louisville School of Medicine, reviewed this article before publication. Thomas J. Wheeler, Ph.D., and Manfred Kroger, Ph.D., helped edit it.